Long-term safety of nebivolol and valsartan combination therapy in patients with hypertension: an open-label, single-arm, multicenter study.

Long-term safety of a free-tablet combination of nebivolol and valsartan was assessed in a Phase III, open-label trial (NCT01415505). Adults with hypertension entered a 4-week placebo run-in phase, followed by a 52-week treatment phase. Initial dosage (Neb/Val 5/160 mg/d) was titrated up to 20/320 mg/d to achieve blood pressure (BP) goal (JNC7 criteria), with the addition of hydrochlorothiazide (up to 25 mg/d) if needed. Safety and tolerability parameters included adverse events. Efficacy assessments included baseline-to-endpoint change in diastolic BP and systolic BP and the percentage of patients who achieved BP goal. All analyses were performed using descriptive statistics. Study completion rate was 60.4% (489/810). The most frequent reason for discontinuation was insufficient therapeutic response (8.4%). Adverse events were experienced by 59.2% of patients, with the most common being headache (5.7%), nasopharyngitis (5.0%), and upper respiratory tract infection (4.6%). Three (0.4%) deaths occurred during the study; none was considered related to study medication. Mean ± standard deviation changes from baseline at week 52 (observed cases) were -25.5 ± 15.9 mm Hg (systolic BP) and -19.0 ± 8.7 mm Hg (diastolic BP). A total of 75.7% nebivolol/valsartan-treated and 57.8% nebivolol/valsartan/hydrochlorothiazide-treated completers achieved BP goal. Long-term treatment with nebivolol and valsartan in adults with hypertension was safe and well-tolerated.

Placebo effect and efficacy of nebivolol in patients with hypertension not controlled with lisinopril or losartan: a phase IV, randomized, placebo-controlled trial.

BACKGROUND: Most patients with hypertension require more than one antihypertensive to achieve blood pressure (BP) control. OBJECTIVE: The purpose of this trial was to assess the efficacy and tolerability of add-on nebivolol, a vasodilatory ß-blocker, in patients with untreated or poorly controlled hypertension, receiving stable therapy with lisinopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin II receptor blocker). STUDY DESIGN: This was a phase IV double-blind, placebo-controlled trial conducted from August 2008 to March 2010 (ClinicalTrials.gov identifier: NCT00734630). Patients entered a 2-week, single-blind, placebo-only washout phase, followed by a 3- to 4-week open-label lead-in phase (lisinopril, 10-20 mg/day, or losartan, 50-100 mg/day), and a 12-week randomized, double-blind add-on treatment phase with placebo or nebivolol (5-40 mg/day). SETTING: This study was conducted at 76 outpatient centers in the United States. PATIENTS: Participants were men and women aged 18-85 years with a diagnosis of primary hypertension and seated trough systolic BP (SBP) at screening in the range of 170-200 mmHg if untreated, 155-180 mmHg if taking 1 antihypertensive medication, or 140-170 mmHg if taking 2 antihypertensive medications. INTERVENTION: The intervention was 12 weeks' treatment with nebivolol 5-40 mg/day added to a background therapy of lisinopril 10-20 mg/day or losartan 50-100 mg/day. MAIN OUTCOME MEASURES: Primary and secondary efficacy parameters were changes from baseline in seated trough cuff SBP and diastolic BP (DBP) at Week 12, respectively. Tolerability was assessed by monitoring treatment-emergent adverse events (TEAEs). RESULTS: A total of 491 patients were randomized to receive nebivolol (n=258) or placebo (n=233). Efficacy analyses were conducted for 256 nebivolol and 232 placebo patients (intent-to-treat population); completion rates were 88.8% and 85.8%, respectively. Mean baseline SBP/DBP values were 163.1/98.2 mmHg (nebivolol) and 162.4/96.8 mmHg (placebo). Nebivolol was associated with a non-significant mean±SD reduction in SBP (-10.1±16.9 mmHg) versus placebo (-7.3±15.9 mmHg, P=0.093) and significant mean DBP reduction (-7.8±10.1 mmHg vs -3.5±10.6 mmHg, P<0.001). Subgroup analysis suggested a significant effect on DBP for patients receiving background losartan treatment (-8.1±9.2 mmHg vs -3.1±9.4 mmHg, P<0.001), but not for those receiving lisinopril (-7.6±10.8 mmHg vs -3.8±11.6 mmHg, P=0.076). A total of 28% nebivolol-treated and 22% placebo-treated patients reported a TEAE, the most frequent being upper respiratory tract infection (4.3% and 2.1%, respectively), bradycardia (2.7% and 0%), headache (2.3% and 2.1%), and nasopharyngitis (2.3% and 0.9%). CONCLUSION: These data suggest that nebivolol, when added to lisinopril or losartan, results in an additional BP reduction; however, only the effect on DBP reached statistical significance. A subanalysis suggests that the effect on DBP may be stronger in losartan-treated than lisinopril-treated patients. A relatively strong placebo effect may limit data interpretation. Nebivolol was well tolerated, as there was no difference in TEAEs between nebivolol and placebo. FUNDING: This trial (NCT00734630) was funded by Forest Laboratories, Inc.

CaRES (Contrast Echocardiography Registry for Safety Surveillance): a prospective multicenter study to evaluate the safety of the ultrasound contrast agent definity in clinical practice.

BACKGROUND: Definity (perflutren lipid microsphere) is an ultrasound contrast agent approved for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. This prospective, open-label, nonrandomized, multicenter, phase 4 surveillance registry study was conducted at 15 clinical sites in the United States and was designed to assess the risk for adverse cardiopulmonary events occurring during or within the initial 30 min after Definity administration in routine clinical practice. METHODS: Patients with suboptimal baseline images were consecutively approached regarding study participation. Safety monitoring including vital sign measurements, continuous electrocardiographic monitoring, and continuous oxygen saturation was initiated at baseline before Definity administration and then at regular intervals for 30 min after Definity injection. Patients were assessed for adverse events at 30 min after Definity administration and then contacted by telephone at 24 ± 4 hours to record any subsequent adverse events. RESULTS: A total of 1,060 patients were enrolled at 15 clinical sites. Of these, 1,053 (99.3%) received at least one dose of Definity and completed the study. No deaths, serious adverse events, or other significant adverse events occurred during this study. The overall adverse event rate was 10.8% (4.5% in patients undergoing rest echocardiography, 13% in patients undergoing rest and exercise stress echocardiography, and 27.7% in patients undergoing rest and pharmacologic stress echocardiography). The overall drug-related adverse event rate (patients with at least one adverse event reported by the principal investigator as related to Definity) was only 3.5%, and most of these (110 of 114 [96.5%]) were reported by the investigator as mild or moderate in intensity. CONCLUSIONS: Definity is well tolerated in routine clinical practice in patients with a high prevalence of cardiopulmonary disease.

Mortality and morbidity during and after the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.

A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and ≥ 1 other coronary heart disease risk factors to receive chlorthalidone (n=15,002), amlodipine (n=8898), or lisinopril (n=8904) for 4 to 8 years, when double-blinded therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up. Primary outcome was cardiovascular mortality and secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels. No significant differences (P<.05) appeared in cardiovascular mortality for amlodipine (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.93-1.06) or lisinopril (HR, 0.97; CI, 0.90-1.03), each compared with chlorthalidone. The only significant differences in secondary outcomes were for heart failure, which was higher with amlodipine (HR, 1.12; CI, 1.02-1.22), and stroke mortality, which was higher with lisinopril (HR, 1.20; CI, 1.01-1.41), each compared with chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone. Black participants had higher risk than non-black participants taking lisinopril compared with chlorthalidone. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension.

Efficacy and tolerability of nebivolol in stage I-II hypertension: a pooled analysis of data from three randomized, placebo-controlled monotherapy trials.

BACKGROUND: Nebivolol is a ß(1)-selective ß-blocker with NO-mediated vasodilatory properties, approved in the United States for the treatment of stage I-II hypertension. OBJECTIVE: The purpose of this pooled analysis was to summarize efficacy and provide a brief overview of the tolerability associated with the use of nebivolol. METHODS: PubMed was searched for randomized, double-blind, placebo-controlled, parallel-group trials of monotherapy with nebivolol for stage I-II hypertension of at least 12 weeks' duration. This article reports pooled changes in sitting diastolic blood pressure (DBP), systolic blood pressure (SBP), and heart rate (HR) at trough; proportions of responders (patients whose end-point sitting DBP at trough was <90 mm Hg or whose sitting DBP at trough had decreased from baseline by ≤10 mm Hg); and the most frequent adverse events (AEs). These data were also summarized in the subpopulation of black patients. RESULTS: The literature search yielded 3 similarly designed studies. In all 3 trials, a single-blind placebo run-in phase (4-6 weeks) was followed by randomization (baseline) and a 12-week double-blind treatment phase in which patients received nebivolol 1.25 to 30 or 40 mg/d or placebo. The primary efficacy measure in all 3 trials was the mean change from baseline in sitting DBP at 12 weeks, based on the intent-to-treat population. In the pooled sample, 930 (46.1%) patients were women, and the mean age was 53.6 years. Compared with placebo (n = 205), the reductions in DBP (up to 11.1 mm Hg), SBP (up to 12.4 mm Hg), and HR (up to 9.2 beats/min) were significantly greater with nebivolol (n = 1811) at the recommended dosages of 5-30/40 mg/d (all, P < 0.001). The most commonly reported AEs were headache (nebivolol, all dosages, 7.1%; placebo, 5.9%), fatigue (3.6% vs 1.5%, respectively), and nasopharyngitis (3.1% vs 4.4%). The efficacy and tolerability of nebivolol in black patients were similar to those observed in the total study population. CONCLUSION: Based on the pooled results from the 3 monotherapy trials reported here, nebivolol administered for 12 weeks was efficacious and generally well tolerated in patients with stage I-II hypertension.

Blood pressure control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

Blood pressure (BP) control rates and number of antihypertensive medications were compared (average follow-up, 4.9 years) by randomized groups: chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) in a randomized double-blind hypertension trial. Participants were hypertensives aged 55 or older with additional cardiovascular risk factor(s), recruited from 623 centers. Additional agents from other classes were added as needed to achieve BP control. BP was reduced from 145/83 mm Hg (27% control) to 134/76 mm Hg (chlorthalidone, 68% control), 135/75 mm Hg (amlodipine, 66% control), and 136/76 mm Hg (lisinopril, 61% control) by 5 years; the mean number of drugs prescribed was 1.9, 2.0, and 2.1, respectively. Only 28% (chlorthalidone), 24% (amlodipine), and 24% (lisinopril) were controlled on monotherapy. BP control was achieved in the majority of each randomized group-a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP <140/90 mm Hg in a majority of patients.

A randomized, double-blind, placebo-controlled parallel-group study to assess the efficacy and safety of nebivolol, a novel beta-blocker, in patients with mild to moderate hypertension.

This double-blind, multicenter, randomized placebo-controlled study evaluated the antihypertensive efficacy and safety of nebivolol, a selective beta1-adrenoreceptor blocker with vasodilating effects, in patients with mild to moderate hypertension (sitting diastolic blood pressure [SiDBP] > or =95 mm Hg and < or =109 mm Hg). A total of 909 patients were randomized to receive placebo or nebivolol 1.25, 2.5, 5, 10, 20, or 40 mg once daily for up to 84 days. The primary end point was the change in trough SiDBP from baseline to study end. Nebivolol significantly reduced trough SiDBP (8.0-11.2 mm Hg compared with 2.9 mm Hg with placebo; P<.001) and trough sitting systolic blood pressure (a 4.4-9.5-mm Hg decrease compared with a 2.2-mm Hg increase [corrected] with placebo; P< or =.002). The overall adverse event experience was similar in the nebivolol (46.1%) and placebo (40.7%) groups (P=.273). Once-daily nebivolol is an effective antihypertensive in mild to moderate hypertensive patients.

Results from a phase II multicenter, double-blind placebo-controlled study of Del-1 (VLTS-589) for intermittent claudication in subjects with peripheral arterial disease.

BACKGROUND: This study compared VLTS-589 (plasmid encoding the angiomatrix protein Del-1 in conjunction with poloxamer 188) with poloxamer 188 control, for the treatment of intermittent claudication in patients with moderate to severe peripheral arterial disease. METHODS: Subjects with bilateral intermittent claudication and peak walking time (PWT) between 1 and 10 minutes on 2 qualifying (reproducible; within 25% of each other) treadmill tests were enrolled. Patients received VLTS-589 or poloxamer 188 control, administered as 21 intramuscular injections to each lower extremity (42 mL in each extremity). In addition to safety and tolerability, efficacy evaluations compared to baseline included the following: change in PWT at 90 days (primary end point), change in claudication onset time, change in ankle brachial index (ABI), and change in quality of life measures. RESULTS: A total of 105 patients were randomized and treated. During the 30, 90, and 180 days follow-up, mean PWT, claudication onset time, and ABI were significantly increased compared to baseline values in both treatment groups with no significant difference between groups in the primary or secondary end points. In addition, both groups demonstrated significantly improved quality of life at follow-up vs baseline, with no significant differences between groups. Serious adverse events were similar in both groups--none were definitely treatment-related. CONCLUSION: Intramuscular delivery of both Del-1 expressing plasmid and the control resulted in significant improvement in exercise capacity compared to baseline at 30, 90, and 180 days. There was no difference in outcome measures associated with the Del-1 plasmid.

Color encoding of endocardial motion improves the interpretation of contrast-enhanced echocardiographic stress tests by less-experienced readers.

BACKGROUND: We hypothesized that color encoding of endocardial motion could aid less-experienced readers in detection of wall-motion abnormalities at rest and stress in patients with poor acoustic windows. METHODS: Color-encoded images (color kinesis) were obtained at rest and peak dobutamine stress in 4 standard views during intravenous infusion of contrast agent in 117 patients with poorly visualized endocardium. In 101 of 117 patients (86%), in whom contrast enhancement allowed endocardial tracking, images were reviewed by two expert readers without color overlays. Each reader graded regional wall motion as normal, abnormal, or uninterpretable, and their consensus grades served as a gold standard. The same images were then reviewed and graded with and without color overlays by 3 cardiology fellows. The accuracy of the interpretation was calculated against the gold standard separately for the 3 vascular territories (left anterior descending, left circumflex, and right coronary arteries) and averaged for the 3 fellows. RESULTS: With the addition of color encoding: (1) the number of uninterpretable segments decreased by 55% at rest and 61% at peak stress; and (2) all 3 fellows reached higher levels of accuracy in all 3 vascular territories both at rest (6%-82% average) and at stress (73%-80%). CONCLUSION: The addition of color encoding of wall motion to contrast-enhanced images obtained in patients with poor acoustic windows during stress tests improves the interpretation of regional left ventricular function by less-experienced readers.

Computerized evaluation of echocardiographic stress tests in patients with poorly visualized endocardium using analysis of color-encoded contrast-enhanced images.

AIMS: We hypothesized that real-time color encoding of contrast-enhanced images would allow objective detection of stress-induced wall motion abnormalities (WMA). METHODS: We studied 117 patients with poorly visualized endocardium undergoing dobutamine stress tests. Color-encoded images (Philips, color kinesis) were obtained at rest and peak stress in four standard views during i.v. infusion of Definity. Images were reviewed without color overlays by two expert readers, who graded regional wall motion as normal or abnormal. In 101/117 patients (86%), in whom contrast enhancement allowed endocardial tracking, regional fractional area changes were calculated from the color overlays, and thresholds for calling a stress-induced WMA were optimized in a randomly selected subgroup of 34 patients (ROC analysis) to achieve maximum agreement with expert grades. This computerized detection of stress-induced WMA was then tested prospectively in the remaining 67 patients, using the expert grades as a "gold standard". RESULTS: 20/67 patients had resting WMA and 13/67 patients developed WMA at peak stress. The automated technique detected stress-induced WMA in at least one vascular territory with a sensitivity, specificity and accuracy of 0.80, 0.65 and 0.69, while the level of agreement between the two experts was 0.62, 0.91 and 0.85, respectively. CONCLUSION: Analysis of color-encoded, contrast-enhanced images allows objective, accurate, automated detection of stress-induced WMA in patients with poor acoustic windows.

Efficacy and safety of fasudil in patients with stable angina: a double-blind, placebo-controlled, phase 2 trial.

OBJECTIVES: This study sought to evaluate the efficacy and safety of fasudil, an orally available rho kinase inhibitor, in patients with stable angina. BACKGROUND: Several small, non-placebo-controlled trials suggest that fasudil reduces myocardial ischemia in patients with stable or vasospastic angina. METHODS: In a multicenter, double-blind, placebo-controlled, randomized trial, the efficacy and safety of fasudil were evaluated in stable angina patients. Of the 206 patients screened, 84 patients with reproducible exercise times were randomized 1:1 to fasudil or placebo. Nitroglycerin as needed and a beta- or calcium-channel blocker were allowed. Fasudil or matching placebo was force-titrated from 20 mg three times daily to 80 mg twice daily with 20 mg twice-daily increments every two weeks. Symptom-limited exercise testing was performed after two, four, six, and eight weeks of treatment. RESULTS: At peak, exercise duration was significantly improved at all visits in both groups, although exercise duration was numerically greater in patients receiving fasudil versus those receiving placebo. Time to > or =1 mm ST-segment depression was increased with fasudil at both peak and trough compared with placebo (172.1 s vs. 44.0 s, p = 0.001, and 92.8 s vs. 26.4 s, p = 0.02, respectively). Fasudil improved Seattle Angina Questionnaire scores. No significant differences in Canadian Cardiovascular Society class, time to angina, or frequency of angina or nitroglycerin use were noted between groups. Fasudil did not affect heart rate or blood pressure, and was well tolerated. CONCLUSIONS: Fasudil up to 80 mg three times daily significantly increased the ischemic threshold of angina patients during exercise with a trend toward increased exercise duration. Further investigation of fasudil doses >80 mg three times daily is indicated.

Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low high-density lipoprotein cholesterol levels.

Patients with combined hyperlipidemia and low high-density lipoprotein (HDL) cholesterol levels may benefit from combination therapy with a statin and niacin; therefore, we assessed the efficacy and safety of rosuvastatin and extended-release (ER) niacin alone and in combination in 270 patients with this atherogenic dyslipidemia. Men and women > or =18 years with fasting total cholesterol levels > or =200 mg/dl, triglycerides 200 to 800 mg/dl, apolipoprotein B > or cf=110 mg/dl, and HDL cholesterol <45 mg/dl were randomized to 1 of 4 treatments in this 24-week, open-label, multicenter trial: rosuvastatin 10 to 40 mg; ER niacin 0.5 to 2 g; rosuvastatin 40 mg/ER niacin 0.5 to 1 g; or rosuvastatin 10 mg/ER niacin 0.5 to 2 g. Percent changes from baseline in low-density lipoprotein (LDL) cholesterol, non-HDL cholesterol, and other lipid measurements at week 24 were determined by analysis of variance, with statistical testing performed separately between the rosuvastatin monotherapy group and each remaining treatment group. Daily doses of rosuvastatin 40 mg reduced LDL and non-HDL cholesterol significantly more than either ER niacin 2 g or rosuvastatin 10 mg/ER niacin 2 g (-48% vs -0.1% and -36% for LDL cholesterol and -49% vs -11% and -38% for non-HDL cholesterol, respectively; p <0.01 for all comparisons); no additional reduction in LDL or non-HDL cholesterol was observed with the combination of rosuvastatin 40 mg/ER niacin 1.0 g (-42% and -47%; p = NS). Triglyceride reductions ranged from -21% (ER niacin monotherapy) to -39% (rosuvastatin 40 mg/ER niacin 1 g), but no observed differences were statistically significant. Compared with rosuvastatin alone, rosuvastatin 10 mg/ER niacin 2 g produced significantly greater increases in HDL cholesterol (11% vs 24%, p <0.001) and apolipoprotein A-I (5% vs 11%, p <0.017). Similar increases in HDL cholesterol and apolipoprotein A-I were noted between the monotherapy groups. Over 24 weeks, rosuvastatin alone was better tolerated than either ER niacin alone or the combinations of rosuvastatin and ER niacin.

Comparison of effects of nisoldipine-extended release and amlodipine in patients with systemic hypertension and chronic stable angina pectoris.

The efficacy and safety of nisoldipine-extended release (ER) and amlodipine were compared in a 6-week multicenter, randomized, double-blind, double-dummy, parallel group, titration-to-effect trial in patients with stage 1 to 2 systemic hypertension (90 to 109 mm Hg diastolic blood pressure [BP]) and chronic stable angina pectoris. After a 3-week placebo run-in period, patients (n = 120) were randomly assigned to active treatment with either nisoldipine-ER (20 to 40 mg) or amlodipine (5 to 10 mg) once daily, titrated as necessary after 2 weeks to achieve diastolic BP <90 mm Hg. After 6 weeks, the mean reduction in systolic/diastolic BP from baseline was 15/13 mm Hg with nisoldipine-ER and 13/11 mm Hg with amlodipine (p = NS/p = NS). Both drugs resulted in similar BP responder rates (diastolic BP <90 mm Hg in 87% of patients who received nisoldipine-ER and 78% of patients on amlodipine, p = NS) and anti-ischemic responder rates (increasing exercise time >20% in 20% and 27%, respectively [p = NS], and increasing exercise time >60 seconds in 32% and 29% of patients, respectively [p = NS]. Also, after 6 weeks of active therapy, there was a similar mean increase in total exercise duration (23 seconds in the nisoldipine-ER group and 21 seconds in the amlodipine group, p = NS). Neither drug increased heart rate and both decreased frequency of anginal episodes. Adverse events were infrequent, and typically were vasodilator-related effects (including headache and peripheral edema) that occurred with somewhat higher incidence in the nisoldipine-ER group. Thus, nisoldipine-ER and amlodipine provided comparable antihypertensive and anti-ischemic efficacy, and both were generally well tolerated.

Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).

CONTEXT: Blood pressure control (<140/90 mm Hg) rates for hypertension fall far short of the US national goal of 50% or more. Achievable control rates in varied practice settings and geographic regions and factors that predict improved blood pressure control are not well identified. OBJECTIVE: To determine the success and predictors of blood pressure control in a large hypertension trial involving a multiethnic population in diverse practice settings. DESIGN: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial is a randomized, double-blind, active-controlled clinical trial with a mean follow-up of 4.9 years. Participant enrollment began in February 1994 and follow-up was completed in March 2002. SETTING: A total of 623 centers in the United States, Canada, and the Caribbean. PARTICIPANTS: A total of 33,357 participants (aged > or =55 years) with hypertension and at least one other coronary heart disease risk factor. INTERVENTIONS: Participants were randomly assigned to receive (double-blind) chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) after other medication was discontinued. Doses were increased within these ranges and additional drugs from other classes were added as needed to achieve blood pressure control (<140/90 mm Hg). MAIN OUTCOME MEASURES: The outcome measures for this report are systolic and diastolic blood pressure, the proportion of participants achieving blood pressure control (<140/90 mm Hg), and the number of drugs required to achieve control in all three groups combined. RESULTS: Mean age was 67 years, 47% were women, 35% black, 36% diabetic; 90% were on antihypertensive drug treatment at entry. At the first of two pre-randomization visits, blood pressure was <140/90 mm Hg in only 27.4% of participants. After 5 years of follow-up, the percent controlled improved to 66%. Systolic blood pressure was <140 mm Hg in 67% of participants, diastolic blood pressure was <90 mm Hg in 92%, the mean number of drugs prescribed was 2.0+/-1.0, and the percent on > or =2 drugs was 63%. Blood pressure control varied by geographic regions, practice settings, and demographic and clinical characteristics of participants. CONCLUSIONS: These data demonstrate that blood pressure may be controlled in two thirds of a multiethnic hypertensive population in diverse practice settings. Systolic blood pressure is more difficult to control than diastolic blood pressure, and at least two antihypertensive medications are required for most patients to achieve blood pressure control. It is likely that the majority of people with hypertension could achieve a blood pressure <140/90 mm Hg with the antihypertensive medications available today.

Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension.

BACKGROUND: Eplerenone, a selective aldosterone blocker (SAB) that is highly specific for the aldosterone receptor, has the potential to be efficacious in the treatment of hypertension. METHODS: This 8-week, multicenter, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of eplerenone in eligible patients randomized to eplerenone 50, 100, or 400 mg once daily; eplerenone 25, 50, or 200 mg twice daily; spironolactone 50 mg twice daily; or placebo. The primary efficacy variable was the adjusted mean change in baseline to final visit for seated diastolic blood pressure (DBP). RESULTS: Of 417 randomized patients, 409 were evaluated for efficacy. The adjusted mean change from baseline to final visit in seated and standing systolic blood pressure (SBP) and DBP was significantly greater (P < .05) in all eplerenone groups than in the placebo group. The adjusted mean change in 24-h ambulatory blood pressure monitoring (ABPM) measurements of SBP and DBP also documented a 24-h duration significantly greater (P < .05) than placebo in eplerenone-treated patients. For all measurements, the antihypertensive effect of eplerenone increased in a dose-response fashion. Eplerenone (100 mg) reduced BP by 75% compared with spironolactone (100 mg) and had an adverse events incidence rate similar to placebo. No antiandrogenic or progestational effects or clinically relevant safety issues were observed in eplerenone-treated patients. However, one spironolactone-treated patient reported menstrual irregularities. CONCLUSIONS: Eplerenone doses of 50 to 400 mg once daily are well tolerated and effective in reducing BP in patients with mild-to-moderate hypertension during a 24-h period.

Efficacy and Safety of Bepridil in Chronic Stable Angina Pectoris Refractory to Nifedipine.

The efficacy and safety of bepridil in chronic stable angina pectoris refractory to an extended-release preparation of nifedipine were evaluated in this open-label prospective study. Patients whose angina had not responded adequately to maximum tolerated doses of nifedipine received bepridil for 8 weeks after a 2-week baseline period at their established dose of nifedipine. Twenty-five patients entered the bepridil treatment period. Total exercise time (mean plus minus SD) was significantly increased at the end of bepridil therapy (9.3 plus minus 2.3 min) compared with the end of nifedipine baseline period (8.40 plus minus 2.3 min, p = 0.02). Time to the onset of angina increased from 6.1 plus minus 2.7 min to 8.1 plus minus 2.3 min, p < 0.01. Time to 1-mm ST depression increased from 7.0 plus minus 2.7 min to 8.4 plus minus 2.3 min, p < 0.01. Nitroglycerin consumption decreased from 3.01 plus minus 5.6 to 0.56 plus minus 1.3 tablets week(minus sign1), p < 0.05. The mean weekly angina attack rate decreased from 4.34 plus minus 5.3 to 1.33 plus minus 2.2, p < 0.01. Therapy with bepridil resulted in few adverse experiences. The mean QT(c) interval was significantly prolonged from 0.40 + 0.03 s at baseline to 0.45 + 0.045 s at the end of bepridil therapy (p < 0.001). There were no serious adverse events. The results of this study indicated that bepridil provides effective and safe treatment of stable angina pectoris in patients whose angina is not adequately controlled by nifedipine.

Perindopril/Hydrochlorothiazide Combination in Hypertensive Patients Unresponsive to Hydrochlorothiazide Alone: A Double-Blind, Multicenter Study.

This study evaluated the efficacy and tolerability of perindopril erbumine, a long-acting ACE inhibitor, added to continuing hydrochlorothiazide (HCTZ) therapy in hypertensive patients (DBP of 95 to 114 mmHg) whose blood pressure did not normalize (supine DBP <90 mmHg) with HCTZ therapy alone. In this multicenter study, 252 patients received HCTZ 25 mg/day for 4 weeks; the 208 whose blood pressure did not normalize entered a 12-week, double-blind segment. These patients continued to receive HCTZ and were randomly assigned to perindopril (2, 4, or 8 mg) or placebo once daily. Mean supine SBP/DBP reductions from baseline for all HCTZ plus perindopril groups were significantly (p less-than-or-equal 0.05) greater than for HCTZ plus placebo. At the start of double-blind treatment, mean supine SBP/DBP readings were 146.1/97.0, 145.4/98.2 and 146.4/98.2 mmHg for the HCTZ plus perindopril 2-, 4-, and 8-mg groups, respectively, and 143.9/96.9 mmHg for HCTZ plus placebo group. At the final visit, mean reductions in supine SBP/DBP were 10.3/6.7, 9.6/8.0, and 9.3/6.3 mmHg for HCTZ plus perindopril 2, 4, and 8 mg, respectively, and 1.6/2.0 mmHg for HCTZ plus placebo. Significantly (p less-than-or-equal 0.05) more HCTZ plus perindopril patients (53.2%) than HCTZ plus placebo patients (24.5%) achieved an adequate response to therapy (supine DBP <90 mmHg or decrease by >10 mmHg). Incidences of adverse experiences were similar among treatment groups. There were no reports of first-dose hypotension. In patients unresponsive to HCTZ alone, the addition of perindopril at doses of 2--8 mg once daily provided safe and effective blood pressure reduction with no added side-effect liability.

Effect of Bisoprolol and Atenolol on Left Ventricular Mass in Patients with Essential Hypertension.

A new beta-blocker, bisoprolol, was compared to atenolol for antihypertensive efficacy and ability to cause regression of left ventricular mass. Twenty-eight patients were randomized into this 8-week, double-blind, dose-escalating trial. Echocardiography was performed in 18 of these patients at baseline and after 8 weeks of therapy to determine left ventricular (LV) mass indices. Both drugs caused a reduction in blood pressure, although bisoprolol caused a significantly greater reduction than did atenolol in diastolic pressure (p < 0.05) and a trend toward a greater reduction in systolic pressure (p < 0.096) as measured by cuff. Comparisons showed a significantly greater reduction in mean LV mass indices with bisoprolol than with atenolol (p < 0.05). A new beta-blocker, bisoprolol, was compared to atenolol for antihypertensive efficacy and ability to cause regression of left ventricular mass. Twenty-eight patients were randomized into this 8-week, double-blind, dose-escalating trial. Echocardiography was performed in 18 of these patients (bisoprolol treated = 8, atenolol treated = 10) at baseline and after 8 weeks of therapy to determine left ventricular (LV) mass indices. Both drugs caused a reduction in blood pressure, although bisoprolol caused a significantly greater reduction than did atenolol in diastolic pressure (p < 0.05) and a trend toward a greater reduction in systolic pressure (p < 0.096) as measured by cuff (bisoprolol means: 152.6 plus minus 9.7/102.8 plus minus 2.8 to 134.0 plus minus 10.0/84.4 plus minus 5.6 mm Hg; atenolol means: 158.4 plus minus 13.8/101.4 plus minus 3.5 to 148.0 plus minus 21.4/91.4 plus minus 5.9 mm Hg). Ambulatory blood pressure monitoring results suggested bisoprolol had longer effectiveness at lowering systolic pressure than did atenol. Comparisons showed a significantly greater reduction in mean LV mass indices with bisoprolol (from 110.0 plus minus 212.3 to 101.8 plus minus 22.0 g m(minus sign2)) than with atenolol (116.9 plus minus 25.5 to 121.7 plus minus 22.2 g m(minus sign2)) (p < 0.05). Bisoprolol was safe and efficacious in blood pressure control and significantly better than atenolol in reducing LV mass.